Type 2 Diabetes: Etiology and Reversibility

Roy Taylor, MD, FRCP

Disclosures

Diabetes Care. 2013;36(4):1047-1055. 

In This Article

The Time Course to Development of Type 2 Diabetes

The earliest predictor of the development of type 2 diabetes is low insulin sensitivity in skeletal muscle, but it is important to recognize that this is not a distinct abnormality but rather part of the wide range expressed in the population. Those people in whom diabetes will develop simply have insulin sensitivity, mainly in the lowest population quartile.[29] In prediabetic individuals, raised plasma insulin levels compensate and allow normal plasma glucose control. However, because the process of de novo lipogenesis is stimulated by higher insulin levels,[38] the scene is set for hepatic fat accumulation. Excess fat deposition in the liver is present before the onset of classical type 2 diabetes,[43,74–76] and in established type 2 diabetes, liver fat is supranormal.[20] When ultrasound rather than magnetic resonance imaging is used, only more-severe degrees of steatosis are detected, and the prevalence of fatty liver is underestimated, with estimates of 70% of people with type 2 diabetes as having a fatty liver.[76] Nonetheless, the prognostic power of merely the presence of a fatty liver is impressive of predicting the onset of type 2 diabetes. A large study of individuals with normal glucose tolerance at baseline showed a very low 8-year incidence of type 2 diabetes if fatty liver had been excluded at baseline, whereas if present, the hazard ratio for diabetes was 5.5 (range 3.6–8.5).[74] In support of this finding, a temporal progression from weight gain to raised liver enzyme levels and onward to hypertriglyceridemia and then glucose intolerance has been demonstrated.[77]

In obese young people, decreased β-cell function has recently been shown to predict deterioration of glucose tolerance.[4,78] Additionally, the rate of decline in glucose tolerance in first-degree relatives of type 2 diabetic individuals is strongly related to the loss of β-cell function, whereas insulin sensitivity changes little.[79] This observation mirrors those in populations with a high incidence of type 2 diabetes in which transition from hyperinsulinemic normal glucose tolerance to overt diabetes involves a large, rapid rise in glucose levels as a result of a relatively small further loss of acute β-cell competence.[3] The Whitehall II study showed in a large population followed prospectively that people with diabetes exhibit a sudden rise in fasting glucose as β-cell function deteriorates (Fig. 5).[80] Hence, the ability of the pancreas to mount a normal, brisk insulin response to an increasing plasma glucose level is lost in the 2 years before the detection of diabetes, although fasting plasma glucose levels may have been at the upper limit of normal for several years. This was very different from the widely assumed linear rise in fasting plasma glucose level and gradual β-cell decompensation but is consistent with the time course of markers of increased liver fat before the onset of type 2 diabetes observed in other studies.[81] Data from the West of Scotland Coronary Prevention Study demonstrated that plasma triacylglycerol and ALT levels were modestly elevated 2 years before the diagnosis of type 2 diabetes and that there was a steady rise in the level of this liver enzyme in the run-up to the time of diagnosis.[75]

Figure 5.

Change in fasting plasma glucose (A), 2 h post-oral glucose tolerance test (B), and homeostasis model assessment (HOMA-B) insulin secretion (C) during the 16-year follow-up in the Whitehall II study. Of the 6,538 people studied, diabetes developed in 505. Time 0 was taken as the diagnosis of diabetes or as the end of follow-up for those remaining normoglycemic. Redrawn with permission from Tabák et al.80

The accepted view has been that the β-cell dysfunction of established diabetes progresses inexorably,[79,82,83] whereas insulin resistance can be modified at least to some extent. However, it is now clear that the β-cell defect, not solely hepatic insulin resistance, may be reversible by weight loss at least early in the course of type 2 diabetes.[21,84] The low insulin sensitivity of muscle tissue does not change materially either during the onset of diabetes or during subsequent reversal. Overall, the information on the inhibitory effects of excess fat on β-cell function and apoptosis permits a new understanding of the etiology and time course of type 2 diabetes.

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